1. Field of the Invention
Cardiac arrhythmias are disorders of impulse generation in the mammalian heart. Although the physiological mechanisms of these disorders are not completely understood, they are believed to result from disruptions of normal cardiac pacemaker activity, disturbances in the cardiac conductive fibers, or a combination of the former and latter factors. Cardiac arrhythmias of clinical significance in man include: (A) premature contractions (extra -systoles) having their origin in abnormal focal points in the atria or ventricles, (B) paroxysmal supraventricular tachycardia, (C) atrial flutter, (D) atrial fibrillation, (E) ventricular tachycardia, and (F) ventricular fibrillation. These arrhythmias can be induced in experimental animals to study physiological mechanisms involved in such arrhythmias or to screen new antiarrhythmic agents.
Arrhythmias are treated clinically by administration of a variety of drugs, although quinidine and procainamide are current mainstays. Quinidine is the d-isomer of quinine while procainamide is p-amino N-(2 -diethylamino-ethyl)-benzamide. Both drugs require extreme care in administration and are considered relatively dangerous. In weighing their efficacy over their danger, however, the former is countervailing. Because of such limitations in currently available antiarrhythmic drugs, there have been efforts to discover safer substitutes. The discovery of the antiarrhythmic activity of hydantoin opened new approaches in the design of new compounds exhibiting such activity. For a general discussion of this field, to which the instant invention pertains, refer to -- G. K. Moe and J. A. Albildskov, "Antiarrhythmic Drugs," in: The Pharmacological Basis of Therapeutics, L. S. Goodman and A. Gilman, Editors, 4th Edition, The MacMillan Company, New York, Chapter 32 (1970).
2. Description of the Prior Art
U.S. Pat. No. 2,409,754 (1954) discloses the synthesis and structures of diphenylhydantoin, or 5,5-diphenyl-2,4-imidazolidinedione, which is represented by Formula I: ##STR1## Diphenylhydantoin (hereafter referred to as DPH) was utilized initially in the treatment of epilepsy, but was discovered later to have important antiarrhythmic applications. Of particular interest to scientists and clinicians was that the pharmacodynamics of DPH differed from quinidine and procainamide, and that DPH did not exhibit the dangerous properties of its precursors. DPH was found specifically to antagonize ventricular arrhythmias induced by digitalis. In its action on the heart, DPH depresses ventricular automaticity, enhances atrio-ventricular nodal conduction, and reduces the effective refractory period. DPH, however, is not without untoward side effects: dizziness, nausea, emesis, nystigmus, and ataxia. Large doses may produce atrio-ventricular blockage, bradycardia, or even cardiac arrest. For a review of the current status of DPH as an antiarrhythmic agent, see -- L. S. Dreifus and Y. Watanabe, Amer. Heart J., 80: 709-713 (1970).
There have been several attempts to improve the activity and to eliminate the side effects of DPH. Henze and Isbell (J. Amer. Chem. Soc., 76: 4152-4156 [1954] described twelve 5-(substituted-phenyl)- and 5,5-di(substituted-phenyl)-hydantoins. Of these compounds, only 5-(4-aminophenyl)-5-phenylhydantoin displayed activity, but only to the extent of 50% of DPH.
W. Chiti and P. Chiarini (11. Farmaco, Sci. Ed., 13: 579-589 [1958]) synthesized seventeen derivatives of DPH, the following three of which are representative:
A. 3-(3-diethylaminopropyl)-5,5-diphenylhydantoin, ##STR2##
B. 3-[3(1-piperidyl)propyl]-5,5-diphenylhydantoin, ##STR3##
C. 3-(3-morpholinopropyl)-5,5-diphenylhydantoin, ##STR4## Chiti and Chiarini did not disclose whether any of their seventeen compounds exhibited antiarrhythmic activity.
The compounds of this invention are more effective in antiarrhythmic activity and cause less cardiac depression than DPH or derivatives II, III, and IV.